The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury

C. Klein, T. Wüstefeld, M.R. Müller, C. Trautwein

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153 Citations (Scopus)

Abstract

Increasing evidence demonstrates that IL-6 has a protective role during liver injury. IL-6 activates intracellular pathways via the gp130 receptor. In order to identify IL-6-gp130 pathways involved in mediating liver protection, we analyzed hepatocyte-specific gp130 knockout mice in a concanavalin A-induced (Con A-induced) model of immune-mediated hepatitis. We demonstrated that IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis. gp130-STAT3 signaling in hepatocytes mediates the IL-6-triggered protective effect. This was demonstrated by analysis of IL-6-induced protection in mice selectively deficient for gp130-dependent STAT1/3 or gp130-SHP2-RAS signaling in hepatocytes. To identify IL-6-gp130-STAT1/3 dependently expressed liver-protective factors, we performed gene array analysis of hepatic gene expression in hepatocyte-specific gp130(-/-) mice as well as in gp130-STAT1/3- and gp130-SHP2-RAS-MAPK-deficient mice. The mouse IL-8 ortholog KC (also known as Gro-alpha) and serum amyloid A2 (SAA2) was identified as differentially IL-6-gp130-STAT3-regulated genes. Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis. In summary, this study defines IL-6-gp130-STAT3-dependent gene expression in hepatocytes that mediates IL-6-triggered protection in immune-mediated Con A-induced hepatitis. Additionally, we identified the IL-6-gp130-STAT3-dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases
Original languageEnglish
Pages (from-to)860-869
JournalThe Journal of Clinical Investigation
Volume115
Issue number4
DOIs
Publication statusPublished - 2005

Keywords

  • tumor-necrosis-factor
  • chronic active hepatitis
  • cytokine receptor gp130
  • concanavalin-a
  • in-vivo
  • rat hepatocytes
  • transgenic mice
  • soluble il-6
  • chemokine kc
  • ifn-gamma

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